Site Navigation

Site Mobile Navigation

Many Rare Mutations May Underpin Diseases

The task of finding the genetic roots of common disease seems much harder, dimming the promise of personal genomics and the chances of quick medical payoffs from the human genome project, given new data about the human genome in two reports published online in the journal Science on Thursday.

It now appears that large numbers of very rare genetic mutations may underlie common human diseases like schizophrenia and cancer. But because the mutations are so rare, costly studies involving large numbers of patients would be needed to identify their role in each disease.

Until recently, rare mutations have been hard to catalog because of the difficulty of distinguishing an unusual mutation from an error in the DNA decoding process.

Now, however, a new generation of decoding machines allows each DNA unit in a genome to be examined 20 or more times, eliminating most errors.

The two reports in Science are particularly extensive surveys which establish that rare mutations are abundant in the human genome. Since most are likely to be deleterious, rare mutations could account for much of the burden of human disease, the authors say.

One of the surveys was conducted by Jacob A. Tennessen and Joshua M. Akey of the University of Washington in Seattle and colleagues, the other by a team led by Matthew R. Nelson and Vincent Mooser of GlaxoSmithKline.

Both groups attribute the abundance of rare variants to the explosion of human populations after the invention of agriculture some 10,000 years ago. Because the population expansion is so recent, in evolutionary terms, natural selection has not had time to eliminate the harmful mutations.

The Seattle team calculates that in every individual, 313 genes out of the 25,000 in the human genome carry rare mutations that alter the function of the protein specified by the gene. The GlaxoSmithKline team, which looked just at a category of genes likely to make good drug targets, calculates that a rare variant occurs in one out of every 17 DNA units, of which the human genome has some three billion.

An error has occurred. Please try again later.

You are already subscribed to this email.

These findings may help explain why it has proved so hard to isolate the genetic roots of disease. Until now, researchers have looked only at common mutations as possible contributors to the risk of common diseases.

This approach was in one sense dictated by technology; for many years, common mutations were the only ones that could be worked with. But a theory developed to justify the approach — the “common disease, common variant” hypothesis — held that some mutations exerted their bad effects late in life, after people had had their children, and had become common because natural selection was powerless to act against them.

But the theory was wrong. Common variants have turned out to explain only a fraction of the genetic risk of common disease. The opposite hypothesis, the “common disease, rare variant” idea, “has become increasingly credible,” the GlaxoSmithKline team writes.

Jonathan Pritchard, a geneticist at the University of Chicago who drew attention to the possible role of rare variants in 2001, said it seemed a likely bet that rare variants were contributing to an important fraction of disease. In addition, many common variants may contribute risks that are too small to have shown up in current surveys, he said. But in either case, detecting the roots of common disease will prove much more difficult than envisaged under the “common variant, common disease” scenario. Mutations with small effect must be studied in large numbers of patients to be detectable. Even if the effects of some rare variants can be measured, assessing the significance of the millions that stud each individual’s genome will be challenging.

Though the cost of decoding an individual’s genome is fast approaching a mere $1,000, the difficulty of interpreting its mutations now seems much greater than before, raising doubts as to how soon genome sequencing will become a routine medical test. But Dr. Pritchard said personal genomics may soon be valuable in specific situations, like pediatric cases, cancer and the genetics of response to drugs.

Another complication underlined by the two new surveys is that many rare mutations, because they are so recent, are specific to particular populations, with Africans and Europeans having sets that do not overlap much. This means that medical knowledge about rare mutations may have to be developed independently for each population.

A version of this article appears in print on May 18, 2012, on Page A22 of the New York edition with the headline: Rare Genetic Mutations May Underpin Diseases. Order Reprints|Today's Paper|Subscribe